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Biomedical subjects

B N Premachandra

Publications and source records attributed to B N Premachandra.

At least 19 recordsLinked to original sources
PubMed1991

Low serum T3 and raised reverse T3 levels in hepatic cirrhosis: role of glucagon.

Hepatic parenchymal tissue is known to be one of the major sites of thyroid hormone metabolism as well as glucagon action. Alterations in circulating thyroid hormone concentrations, as well as hyperglucagonemia, are well documented in subjects with hepatic cirrhosis and advanced liver dysfunction. Also, we have documented recently that hyperglucagonemia induced in normal subjects alters thyroid hormone metabolism, with lowering of serum T3 and a rise in serum reverse T3 (rT3) levels. Thus, it is conceivable that rising glucagon concentrations are responsible for altered thyroid hormone levels in hepatic cirrhosis. To examine this hypothesis, this study determined relationships between plasma glucose, glucagon, insulin, and insulin:glucagon ratio on one hand, and thyroid hormone concentrations on the other, in 51 subjects with hepatic cirrhosis. Significant negative correlations were noted between plasma glucagon and serum T3 (r = -0.418, p less than 0.001) as well as T3:T4 ratio (r = -0.627, p less than 0.0001), whereas significant positive correlations were observed between plasma glucagon and serum rT3 (r = 0.504, p less than 0.001) as well as rT3:T4 ratio (r = 0.644, p less than 0.0001). No such significant relationships were noted between either insulin, glucose and insulin:glucagon ratio on one hand and any of thyroid hormone indices on the other. Therefore, this study indicates that, in hepatic cirrhosis, circulating glucagon concentrations may play a major contributing role in induction of altered serum thyroid hormone concentration by influencing thyroid hormone metabolism.

Adult↗
PubMed1989

Persistence of low serum thyroid hormone levels in a Graves' disease patient receiving supraphysiologic L-thyroxine replacement therapy.

A patient with Graves' disease was treated with radioactive iodine. For several years following treatment, the patient displayed clinical hypothyroidism and persistently low serum thyroxine (T4) and triiodothyronine (T3) levels despite large T4 replacement dosage (0.3-0.4 mg L-thyroxine daily). A defect in T4 absorption was considered unlikely since absorption of fat soluble materials (vitamins A and E) was essentially normal as reflected by their serum concentrations. Abnormalities in serum protein binding of T4 especially by immunoglobulins were suspected; however, thyroid hormone binding antibodies were absent. Thyroxine binding prealbumin (TBPA) levels were either frankly elevated or in the upper normal range and such variations were mirrored by retinol binding protein (RBP) concentrations. Thyroxine binding globulin (TBG) concentration was normal. A surprising finding was an elevated percent dialyzable thyroxine (.041%; normal range, .018-.034%) in spite of a normal concentration of TBG. Serum free fatty acid levels were also elevated. The marked increase in percent free T4 (FT4) fraction together with a low serum total T4 concentration resulted in normal or marginally elevated FT4 levels. An increase in T4 metabolic clearance as suggested by the elevated percent FT4 fraction was corroborated by steady state serum T4 values observed following changes in T4 dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

Female↗
PubMed1988

Coexistence of familial dysalbuminemic hyperthyroxinemia with familial hypercholesterolemia and multiple lipoprotein type hyperlipidemia.

Familial dysalbuminemic hyperthyroxinemia (FDH), an autosomal disorder characterized by an increase in serum albumin binding of thyroxine, has been encountered in a family who was also found to have both familial hypercholesterolemia (FHC) and multiple lipoprotein type hyperlipidemia (MLH). One subject with FHC and two subjects with MLH had FDH. Although some of the laboratory parameters in hyperlipidemic patients with FDH were suggestive of hyperthyroidism, the dialyzable free thyroxine concentrations were in the normal range and the patients were clinically euthyroid. The significance of the occurrence of FDH in hyperlipidemic subjects with hypothyroidism has been discussed, especially in regard to the longer time interval that may be needed to achieve an amelioration of the hypothyroid state during treatment with a normal maintenance dose of thyroxine. Treatment of FDH patients with other drugs may require an altered dosage if the drug binds to the atypical albumin fragments characterizing this disorder.

Genes, Dominant↗
PubMed1988

Decline of T3 and elevation in reverse T3 induced by hyperglucagonemia: changes in thyroid hormone metabolism, not altered release of thyroid hormones.

Recently we reported that hyperglucagonemia induced by glucagon infusion causes a decline in serum Triiodothyronine (T3) and a rise in reverse T3 (rT3) in euthyroid healthy volunteers. These changes in T3 and rT3 levels were attributed to altered T4 metabolism in peripheral tissues. However, the contribution of altered release of thyroid hormones by the thyroid gland could not be excluded. Since the release of thyroid hormones is suppressed by exogenous administration of L-thyroxine (L-T4) in appropriate dosage, we studied thyroid hormone levels for up to 6 hours after intravenous administration of glucagon in euthyroid healthy subjects after administration of L-T4 for 12 weeks. A control study was conducted using normal saline infusion. Plasma glucose rose promptly following glucagon administration demonstrating its physiologic effect. Serum T4, Free T4 and T3 resin uptake were not altered during both studies. Glucagon infusion induced a significant decline in serum T3 (P less than 0.01) and a marked rise in rT3 (P less than 0.01) whereas saline administration caused no alterations in T3 or rT3 levels. Thus the changes in T3 and rT3 were significantly different during glucagon study when compared to saline infusion. (P less than 0.01 for both comparisons). Therefore, this study demonstrates that changes in serum T3 and rT3 caused by hyperglucagonemia may be secondary to altered thyroid hormone metabolism in peripheral tissues and not due to altered release by the thyroid gland, since the release of thyroid hormones is suppressed by exogenous L-T4 administration.

Adult↗
PubMed1987

Immunopathological studies on thyroid immunity. IX. Thyroid and renal amyloidosis in thyroglobulin immunized rabbits.

In serial studies of immunopathologic changes in an animal model of thyroiditis 52 rabbits were immunized with either bovine, porcine or human thyroglobulin (Tg) in Freund's complete adjuvant, while another 47 animals served as noninjected or adjuvant injected controls. The immunized animals were divided into two groups, one receiving an initial series of only three Tg injections while the other received, in addition, challenging injections over an 8-week period. The immunized animals were killed over a period of 6-34 months after the last Tg injection, and untreated controls were killed at comparable ages. In Tg immunized animals, lymphocytic thyroiditis was encountered in 25 per cent and thyroid amyloid in 17 per cent; glomerular amyloid was encountered in 44 per cent with diffuse lesions in 8 per cent, nodular lesions in 17 per cent and a mixture of the two in 19 per cent. That the thyroid and glomerular hyaline deposits contained amyloid was shown by various histochemical criteria, as well as by the presence of typical fibrils on electron microscopy. Immunohistochemical studies indicated that the amyloid was predominantly of the AA type. Rabbits receiving challenging Tg injections, in addition to the initial series, showed only thyroiditis and nodular glomerular lesions most of which were amyloid. Whilst the vast majority of rabbits with lymphocytic or amyloidotic responses showed both thyroid and renal lesions, a small percentage of animals showed only a lesion of one or the other of these two organs. It is of interest that the thyroid and renal amyloid lesions, described for the first time with induced thyroglobulin immunity, were not detected in other earlier short term investigations.

Amyloidosis↗
PubMed1987

Lowering of T3 and rise in reverse T3 induced by hyperglucagonemia: altered thyroid hormone metabolism, not altered release of thyroid hormones.

Recently we reported that hyperglucagonemia induced by glucagon infusion causes a decline in serum T3 and a rise in reverse T3 in euthyroid healthy volunteers. These changes in T3 and rT3 levels were attributed to altered T4 metabolism in peripheral tissues. However, the contribution of altered release of thyroid hormones by the thyroid gland could not be excluded. Since the release of thyroid hormones is inhibited in primary hypothyroidism and is almost totally suppressed following L-thyroxine replacement therapy, we studied thyroid hormone levels for up to 6 hours after intravenous administration of glucagon in subjects with primary hypothyroidism who were rendered euthyroid by appropriate L-thyroxine replacement therapy for several years. A control study was conducted using normal saline infusion. Plasma glucose rose promptly following glucagon administration demonstrating its physiologic effect. Serum T4, Free T4, and T3 resin uptake were not altered during both studies. Glucagon infusion induced a significant decline in serum T3 (P less than 0.05) and a marked rise in rT3 (P less than 0.05) whereas saline administration caused no alterations in T3 or rT3 levels. Thus the changes in T3 and rT3 were significantly different during glucagon study when compared to saline infusion. (P less than 0.01 for both comparisons). Since, the release of thyroid hormones is suppressed by exogenous LT4 administration in these subjects; we conclude that changes in serum T3 and rT3 observed following glucagon administration reflect altered thyroid hormone metabolism in peripheral tissues and not altered release by the thyroid gland.

Adult↗
PubMed1987

Hypothyroxinemia in cardiac arrest.

Thyroid function was evaluated in cardiac arrest (CA), a condition associated with marked activation of the pituitary-adrenal axis. Blood samples were obtained in 24 patients immediately after diagnosis of CA and again ten minutes later. Samples were also obtained from 22 patients admitted consecutively to the intensive care unit (ICU). Abnormalities of thyroid indexes among patients on the ICU who had not experienced CA were low triiodothyronine (T3) in 45%, low thyroxine (T4) in 32%, low free T4 (equilibrium dialysis) in 21%, and elevated reverse T3 levels in 36%. The alterations of thyroid values were both more common and marked in patients with CA, with abnormally low T3 in 84% of the patients, low T4 in 65%, low free T4 in 65%, and high reverse T3 in 80%. Thyroxine-binding globulin and prealbumin concentrations were below the normal range in 40% and 21% of patients with CA. A thyroid hormone-binding inhibitor was detected in 38% of patients with CA. Thyroglobulin level was slightly high in patients with CA but not significantly different from controls on the ICU. The abnormalities present at zero minutes were further exaggerated ten minutes after CA. We conclude that abnormalities on tests measuring thyroid function are extremely common during the cardiovascular emergency of CA.

Adult↗
PubMed1986

Modulation of thyroid parameters by exogenous thyroxine in familial dysalbuminemic hyperthyroxinemia.

A patient with familial dysalbuminemic hyperthyroxinemia (FDH) was given graded doses of exogenous thyroxine (0.2 mg/d for 2 weeks; 0.4 mg/d for 2 weeks; 0.6 mg/d for 2 weeks) to study modulation of various thyroid parameters. The plasma concentration of the serum transport proteins, thyroxine binding globulin (TBG), sex hormone binding globulin (SHBG), and cortisol binding globulin (CBG) as well as serum thyroxine (T4), triiodothyronine (T3), absolute free thyroxine (FT4), and serum protein binding of T4 tracer were measured. At the end of T4 treatment, T4 and T3 were increased by 151% and 78%, respectively. The FT4 increased (157%), while the percent dialyzable free T4 fraction (DFT4) showed no significant change. SHBG, a protein sensitive to thyroid hormone (TH) action, increased 148% (from 0.23 to 0.57 micrograms/dL) after treatment but this concentration was still in the normal range; TBG and CBG decreased by about 16%. Analysis of the electrophoretic 125I-T4 distribution pattern in serum during T4 treatment showed essentially no change in TBG-bound T4 (percent tracer carriage X total T4), while there was a progressive increase in albumin-bound T4 (341% increase over pretreatment value) and a lesser increase in prealbumin (TBPA)-bound T4 (187%). These observations describing alterations in TH action, serum T4-protein binding, and the failure of percent DFT4 to increase with elevation in serum total T4 are of clinical significance in evaluating thyroid function parameters in FDH patients undergoing TH treatment.

Adult↗
PubMed1985

Potentiation of thyroxine 5-deiodination by aminotriazole.

Aminotriazole, a goitrogen, in addition to its known inhibitory effects on the thyroid, demonstrated a unique effect on peripheral deiodination of thyroxine (T4). In contrast to the well-known peripheral effects of goitrogens such as propylthiouracil in inhibiting 5'-deiodinase activity, i.e., to effect a decrease in T4 to triiodothyronine (T3) conversion, aminotriazole had no effect on the 5'-deiodinative pathway. Rather, this goitrogen appeared to stimulate the alternative pathway, viz. T4 5-deiodination, resulting in an increased reverse triiodothyronine (rT3) serum concentration. This was shown in comparisons of serum T4, T3 and rT3 concentrations and serum T3/T4 and rT3/T4 ratios between rats treated with aminotriazole and T4, and rats treated with T4 alone. The finding that aminotriazole may specifically enhance T4 5-deiodination, independently of T4 5'-deiodination, is novel, as this has not been observed in the case of other goitrogens. It is of interest that this goitrogen is devoid of sulphur, which is a prominent constituent of thiourylene compounds which have been noted to affect 5'-deiodination. The potentiating effect of aminotriazole on 5-deiodination of T4 was not attributable to dietary factors.

Amitrole↗
PubMed1985

Glucagon administration induces lowering of serum T3 and rise in reverse T3 in euthyroid healthy subjects.

Euthyroid sick syndrome is characterized by low serum T3 and raised reverse T3 (rT3). Most of the states with this syndrome are also documented to manifest hyperglucagonemia. Furthermore, several recent studies have suggested that glucagon may play a role in T4 monodeiodination in some of these states such as starvation and uncontrolled diabetes mellitus. Therefore, hyperglucagonemia was induced by intravenous glucagon administration in euthyroid healthy volunteers and thyroid hormone levels were determined at frequent intervals up to six hours. Plasma glucose and insulin rose promptly on glucagon administration, thus establishing the physiologic effect of glucagon. Serum T4, free T4, T3 resin uptake, and TSH concentrations remained unaltered throughout the study period. Serum T3 declined to a significantly low level (P less than 0.05) between 60-90 minutes. Serum rT3 rose significantly (P less than 0.05) by four hours and the rise was progressive till the end of the study period. Therefore, these results suggest that hyperglucagonemia may be one of the factors responsible for lowering of T3 and a rise in rT3 in euthyroid sick syndrome.

Female↗
PubMed1985

Transport of thyroxine bound to human prealbumin into rat liver.

The transport into rat liver of thyroxine (T4) bound to human prealbumin was studied with the use of sera obtained from patients with thyroid hormone-binding globulin (TBG) deficiency and with purified human prealbumin. The unidirectional extraction of 125I-T4 by liver was measured after rapid injection of isotope mixed in human serum into the portal vein of ketamine-anesthetized rats. The percentage of total serum T4 transported into liver was 47.6 +/- 5.2% in subjects with TBG deficiency, and this represented a 50% increase in hepatic T4 transport relative to control human serum. Since T4 is bound to albumin and to prealbumin in complete TBG deficiency, these results suggested that T4 bound to human prealbumin was transported into rat liver. This was confirmed using portal vein injections of human prealbumin at physiological concentrations (0.1-0.3 mg/ml). At these concentrations, T4 bound to human prealbumin was readily transported into liver. These studies suggest factors present in the liver microcirculation inhibit the binding of T4 to human prealbumin such that T4 bound to human prealbumin is highly transportable in liver; conversely, T4 bound to rat prealbumin is not transportable in rat liver. The inability of human prealbumin to sequester T4 in plasma may provide the basis for the selective advantage in humans of TBG, which does sequester T4 in plasma.

Adult↗
PubMed1985

Hepatic bioavailability of thyroxine and testosterone in familial dysalbuminemic hyperthyroxinemia.

The bioavailability of [125I]T4 or [3H]testosterone in serum obtained from normal subjects and from subjects with familial dysalbuminemic hyperthyroxinemia (FDH) was studied with a portal vein injection technique in ketamine-anesthetized rats. In the present studies this technique was modified by performing uptake measurements in the presence of serum loaded with either 25 microM T4 or 1 microM testosterone. Loading of serum with these high concentrations displaced the labeled hormone from the lower capacity globulin or prealbumin-binding sites to the high capacity albumin or dysalbumin-binding sites, and allowed for the analysis of hormone availability in liver when the labeled hormone was delivered to the tissue bound either to albumin or to dysalbumin binding sites. In the presence of normal serum, 33 +/- 3% (SE) of T4 was available to rat liver, as opposed to 20 +/- 2% for FDH serum. When normal serum was loaded with 25 microM T4, the bioavailable T4 increased to 97 +/- 2%, consistent with the availability of T4 bound to albumin. However, the hepatic bioavailability of T4 in the presence of 25 microM T4 in FDH serum was only 33 +/- 4%. Testosterone bioavailability was similar in normal and in FDH sera, and was 49 +/- 7% in the absence and 99 +/- 4% in the presence of 1 microM testosterone. These studies suggest that T4 bound to the FDH albumin binding site is not readily available for entry into liver, whereas T4 bound to the normal albumin binding site is freely available for uptake in vivo. The differential bioavailability of T4 is compatible with the model that the normal and FDH binding sites are situated on different parts of the albumin molecule, and that only T4 bound to the normal binding site is freely available for delivery to the liver.

Animals↗
PubMed1984

Ethanol feeding and thyroid hormone monodeiodination.

Adult male rats were placed on a 3 week regimen of ethanol (as 20% of total calories) in a nutritionally adequate diet, and controls were matched equicalorically without ethanol. Serum measurements of T4, T3, FT4, rT3, and TSH were performed in both the fed and the fasted state (18 hours). In the fed state, serum hormone measurements did not differ between control and ethanol-treated rats. Overnight fasting had a significant effect in decreasing serum T3 level in both experimental and control rats and in decreasing serum T4 level in ethanol-treated animals; FT4 and rT3 levels were not affected. Fasting also decreased in vitro hepatic T4 to T3 production to an equivalent degree in control and ethanol-treated rats, but did not alter hepatic T4 to rT3 production rates in control animals. In the fed state, hepatic rT3 neogenesis in animals given ethanol declined relative to the levels observed in control fed rats; fasting restored the depressed rT3 neogenesis to the levels noted in the fed state. Because decreased rT3 production in ethanol-treated rats in the fed state could not be explained on the basis of a change in 5'-deiodinase activity, it is suggested that ethanol administered with a nutritionally adequate diet may inhibit hepatic rT3 generation by inhibiting T4(5)-deiodinase.

Analysis of Variance↗
PubMed1984

Low triiodothyronine and raised reverse triiodothyronine levels in patients over fifty years of age who have type II diabetes mellitus: influence of metabolic control, not age.

Several studies have demonstrated that the uncontrolled diabetic state in both type I as well as type II diabetes mellitus is characterized by altered thyroid hormone metabolism, which results in the lowering of serum triiodothyronine (T3) levels and a reciprocal elevation of T3 (rT3) levels. Because the majority of type II diabetics are over 50 years of age and because numerous previous reports have implicated aging as a cause of low T3 and high rT3 levels, we studied 220 type II diabetics from 40-85 years of age to assess the influence of aging and metabolic control on thyroid hormone levels. Serum thyroxine (T4) free T4, T3 resin uptake, and thyroid-stimulating hormone (TSH) measurements in diabetic patients were not significantly altered compared with 37 young normal control subjects, irrespective of age or the grade of metabolic control. Serum T3 levels declined and rT3 levels rose in the diabetic patients with worsening of the metabolic control. However, with comparable metabolic control, the levels were not significantly different from the younger patients. Therefore, low T3 and high rT3 levels observed in patients of any age who have type II diabetes mellitus may be exclusively caused by deranged metabolic control of their disease.

Adult↗